DESCRIPTION: Epidemiological studies conducted over the last several decades consistently show that light to moderate alcohol consumption protects the heart against coronary artery disease. The major protective properties of alcoholic beverages reside with ethanol itself rather than with bioflavinoids/ antioxidants present in some of these beverages, although the latter may possess certain beneficial biological properties distinct from ethanol. Historically, this protection has been attributed to an ethanol-induced increase in one of the subfractions of HDL in plasma; however, this increase in HDL is now regarded to account for only a minor part of the observed protection by ethanol. The antithrombotic properties of alcohol also continue to it beneficial effect, but a specific molecular mechanism connecting these properties to alcohol has not been forthcoming. We are proposing that nitric oxide (NO) mediates the protective effects of ethanol on the cardiovasculature, including the antithrombotic properties of ethanol, through the NO-cyclic GMP (cGMP) signal transduction pathway. According to our mechanism, protection by ethanol occurs via an enhancement of the NO activation of guanylate cyclase by products of ethanol metabolism. The key specific objectives of this proposal are to show that (a) ethanol metabolism promotes the catalase-catalyzed oxidation of NO to NO2 and (b) NO2 is a more potent activator of guanylate cyclase than NO itself. We propose that ethanol drives the catalase-mediated NO oxidation reaction via a cascade of well established metabolic conversions that result in increased production of hydrogen peroxide. The two-electron oxidation of NO to NO2 by catalase and the subsequent activation of guanylate cyclase by NO2 are two biochemical steps that we have undertaken to establish as fact. These two steps are critical to our understanding of the overall mechanism for the protection of the cardiovasculature provided by ethanol. Moreover, because ethanol and its metabolites as well as NO alter or regulate cellular processes in almost every tissue and body organ, we anticipate that the biochemical mechanisms described here for the interaction between ethanol and the NO-cGMP signaling pathway likely have relevance beyond the cell types located within the cardiovascular system.